Adv Sci (Weinh). 2026 Aug 25:e77156. doi: 10.1002/advs.77156. Online ahead of print.
ABSTRACT
A central challenge in neural repair is the "calcium paradox": while Ca2+ is essential for neuronal growth, global elevations often trigger toxicity rather than repair. Spontaneous near-membrane Ca2+ microdomains (smCa) have been identified in sensory neurons, yet their molecular origin and functional role in repair remain unclear. Here, by resolving Ca2+ dynamics at sub-cellular resolution, we show that TRPC3 drives smCa hotspots, which function as a localized signaling module that avoids global toxicity to instruct repair. Using peripheral sensory neurons as a primary model, we show that TRPC3-smCa constitutes a basic instructive unit that appears both necessary and sufficient to initiate axon regeneration, a process that involves calmodulin-dependent pathways. Following sciatic nerve injury, TRPC3-smCa axis is essential for structural and functional recovery. Our data further suggest that this repair module also operates in central nervous system: in midbrain dopaminergic neurons, TRPC3-smCa is associated with a neuroprotective state, correlating with enhanced neuronal survival and motor function in a Parkinson's disease model. This pro-repair correlation is further observed in human ESC-derived dopaminergic neurons. Collectively, our findings identify TRPC3-driven Ca2+ microdomains as a repair module, pointing to a spatial logic for neural repair with potential relevance for nerve injury and neurodegenerative disorders.
PMID:42640085 | DOI:10.1002/advs.77156